The invention relates to the treatment of neoplastic disorders such as cancer.
Cancer is a disease marked by the uncontrolled growth of abnormal cells. The abnormal cells may no longer do the work of normal cells, and they crowd out and destroy healthy tissue.
Lung cancer is the most common cancer-related cause of death among men and women. It is the second most commonly occurring cancer among men and women; it has been estimated that there will be more than 164,000 new cases of lung cancer in the U.S. in the year 2000 alone. While the rate of lung cancer cases is declining among men in the U.S., it continues to increase among women. Lung cancer can be lethal; according to the American Lung Association, an estimated 156,900 Americans are expected to die due to lung cancer in 2000.
Cancers that begin in the lungs are divided into two major types, non-small cell lung cancer and small cell lung cancer, depending on how the cells appear under a microscope. Non-small cell lung cancer (squamous cell carcinoma, adenocarcinoma, and large cell carcinoma) generally spreads to other organs more slowly than does small cell lung cancer. Small cell lung cancer is the less common type, accounting for about 20% of all lung cancer.
Other cancers include brain cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, kidney cancer, leukemia, liver cancer, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, sarcoma, skin cancer, testicular cancer, and uterine cancer. These cancers, like lung cancer, are sometimes treated with chemotherapy.
Chemotherapeutic drugs currently in use or in clinical trials include paclitaxel, docetaxel, tamoxifen, vinorelbine, gemcitabine, cisplatin, etoposide, topotecan, irinotecan, anastrozole, rituximab, trastuzumab, fludarabine, cyclophosphamide, gentuzumab, carboplatin, interferon, and doxorubicin. The most commonly used anticancer agent is paclitaxel, which is used alone or in combination with other chemotherapy drugs such as: 5-FU, doxorubicin, vinorelbine, cytoxan, and cisplatin.
We have discovered that the combination of the antipsychotic drug chlorpromazine and the antiprotozoal drug pentamidine exhibits substantial antiproliferative activity against cancer cells. Structural and functional analogs of each of these compounds are known, and any of these analogs can be used in the antiproliferative combination of the invention. Metabolites of chlorpromazine and pentamidine are also known. Many of these metabolites share one or more biological activities with the parent compound and, accordingly, can also be used in the antiproliferative combination of the invention. Accordingly, the invention features a method for treating a patient having a cancer or other neoplasm, by administering to the patient chlorpromazine and pentamidine simultaneously or within 14 days of each other in amounts sufficient to inhibit the growth of the neoplasm.
Preferably, the two compounds are administered within ten days of each other, more preferably within five days of each other, and most preferably within twenty-four hours of each other or even simultaneously. The cancer treated according to any of the methods of the invention, described below, can be lung cancer (squamous cell carcinoma, adenocarcinoma, or large cell carcinoma), brain cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, kidney cancer, leukemia, liver cancer, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, sarcoma, skin cancer, testicular cancer, or uterine cancer.
In a related aspect, the invention also features a method for treating a patient having a neoplasm such as cancer. In this method, the patient is administered (a) a first compound selected from prochlorperazine, perphenazine, mepazine, methotrimeprazine, acepromazine, thiopropazate, perazine, propiomazine, putaperazine, thiethylperazine, methopromazine, chlorfenethazine, cyamemazine, perphenazine, enanthate, norchlorpromazine, trifluoperazine, thioridazine (or a salt of any of the above), and dopamine D2 antagonists (e.g., sulpride, pimozide, spiperone, ethopropazine, clebopride, bupropion, and haloperidol); and (b) a second compound selected from propamidine, butamidine, heptamidine, nonamidine, stilbamidine, hydroxystilbamidine, diminazene, benzamidine, 4,4xe2x80x2- (pentamethylenedioxy) di-, dihydrochloride, phenamidine, dibrompropamidine, 1,3-bis(4-amidino-2-methoxyphenoxy)propane, phenamidine, and amicarbalide (or a salt of any of the above). Alternatively, the second compound can be a functional analog of pentamidine, such as netropsin, distamycin, bleomycin, actinomycin, or daunorubicin. The first and second compounds are preferably administered simultaneously or within 14 days of each other and in amounts sufficient to inhibit the growth of the neoplasm.
In another related aspect, the invention also features a method for treating a patient having a neoplasm such as cancer by administering the following:
a) a first compound having the formula (I): 
wherein R2 is selected from the group consisting of: 
R10 is selected from the group consisting of: 
each of R1, R3, R4, R5, R6, R7, R8, and R9 is, independently, H, F, OH, OCF3, or OCH3; and W is selected from the group consisting of: 
and
b) a second compound having the formula (II): 
wherein each of Y and Z is, independently, O or N; each of R11 and R12 is, independently, H, OH, Cl, Br, OCH3, OCF3, NO2, or NH2; n is an integer between 2 and 6, inclusive; and each of R13 and R14 is, independently, at the meta or para position and is selected from the group consisting of: 
wherein the first and second compounds are administered simultaneously or within 14 days of each other in amounts sufficient to inhibit the growth of the neoplasm.
In any of the foregoing treatments, each compound that is part of the combination is preferably administered to the patient as part of a pharmaceutical composition that also includes a pharmaceutically acceptable carrier. Chlorpromazine is preferably administered at a dosage of 10 to 2500 milligrams and pentamidine is preferably administered at a dosage of 1 to 1000 milligrams. Preferred modes of administration include intravenous, intramuscular, inhalation, and oral administration.
The antiproliferative combinations of the invention can be part of a pharmaceutical pack. Preferably, the chlorpromazine and pentamidine are formulated together or separately and in individual dosage amounts.
It will be understood by those in the art that the compounds are also useful when formulated as salts. For example, as is described herein, the isethionate salt of pentamidine exhibits synergistic antiproliferative activity when combined with chlorpromazine. Other salts of pentamidine include the platinum salt, the dihydrochloride salt, and the dimethanesulfonate salt (see, for example, Mongiardo et al., Lancet 2:108, 1989). Similarly, chlorpromazine salts include, for example, hydrochloride salts and maleate salts.
The invention also features methods for identifying compounds useful for treating a patient having a neoplasm. The method includes the steps of contacting cancers cell in vitro with (i) pentamidine or chlorpromazine and (ii) a candidate compound, and determining whether the cancer cells grow more slowly than (a) cancer cells contacted with the chlorpromazine or pentamidine but not contacted with the candidate compound, and (b) cancer cells contacted with the candidate compound but not with chlorpromazine or pentamidine. A candidate compound that, when combined with chlorpromazine or pentamidine, reduces cell proliferation but, in the absence of chlorpromazine or pentamidine, does not is a compound that is useful for treating a patient having a neoplasm.
Combination therapy may be provided wherever chemotherapy is performed: at home, the doctor""s office, a clinic, a hospital""s outpatient department, or a hospital. Treatment generally begins at a hospital so that the doctor can observe the therapy""s effects closely and make any adjustments that are needed. The duration of the combination therapy depends on the kind of cancer being treated, the age and condition of the patient, the stage and type of the patient""s disease, and how the patient""s body responds to the treatment. Drug administration may be performed at different intervals (e.g., daily, weekly, or monthly) and the administration of each agent can be determined individually. Combination therapy may be given in on-and-off cycles that include rest periods so that the patient""s body has a chance to build healthy new cells and regain its strength.
Depending on the type of cancer and its stage of development, the combination therapy can be used to treat cancer, to slow the spreading of the cancer, to slow the cancer""s growth, to kill or arrest cancer cells that may have spread to other parts of the body from the original tumor, to relieve symptoms caused by the cancer, or to prevent cancer in the first place. Combination therapy can also help people live more comfortably by eliminating cancer cells that cause pain or discomfort.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.